Mar

31

Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke.

According to an article published in PLoS Genetics (20 March 2014), a study of the genomes of nearly 5,000 people has pinpointed a genetic variant tied to an increased risk for stroke, as well as new details about an important metabolic pathway that plays a major role in several common diseases. Together, these findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies. This study was supported by theNational Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program.

The study focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when. But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels — and methionine metabolism gone awry — are not well defined.

As a result, the authors conducted genome-wide association studies (GWAS) of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism – the ability to convert methionine to homocysteine – in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.

In a GWAS, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait — the ability to metabolize methionine into homocysteine. Results from the study identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one — the ALDH1L1 gene — was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival. The authors also made important discoveries about the methionine-homocysteine process. According to the authors, the GNMT gene produces a protein that converts methionine to homocysteine, and of the 5 genes that were identified, it was the one most significantly associated with this process. The authors added that the study results suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.

The study determined that the 5 genes accounted for 6% of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13% of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5% of such differences.

The authors stated that this is a great example of the kinds of successful research efforts coming out of the GARNET program, in that the goal of the program is to identify variants that affect treatment response by doing association studies in randomized trials. The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease.